Massive search finds micro RNAs that help the heart regrow.

Heart attacks cause both long- and short-term problems. In the short-term, the death of cardiac muscle cells can cause a critical drop in the heart's ability to function. Over the long haul, problems arise because the damage is largely repaired by scar tissue, rather than functional muscle. For the most part, once cardiac muscle cells stop dividing (in most species, this occurs shortly after birth), they don't ever start again. That means that once they're lost in a heart attack the damage is essentially permanent.

That's why stem cells are often proposed as a treatment for damaged hearts—they provide a way to create new cardiac muscle cells, essentially by recapitulating the process that creates them as an embryo is developing. But there is a potential alternative route: restarting cell divisions within the remaining population of cardiac muscle cells. Some researchers at the University of Trieste may have found a way to do precisely that.

The team reasoned that regulatory RNAs are able to control the expression of a number of genes at once and, unlike proteins, they're a lot easier to get into living cells. So, they focused on a class of short sequences called micro-RNAs (these recently found their way into headlines due to their role in human evolution). Reasoning that some of them are probably involved in controlling cell division, the authors set out to find those by testing about as many as they could.

After searching a database for previously identified micro-RNAs, the team synthesized nearly 900 of them and inserted them into rat cardiac muscle cells that were isolated shortly after birth, when the cells still divide a bit. Once the RNA was in place, they waited for several days, then looked for indications that the cells had started dividing again. About 200 of the RNAs passed this initial test (meanwhile, over 300 RNAs were identified that seemed to shut cell division down). They were then tested on mouse cardiac cells to determine whether their effect was likely to be conserved across evolution. Only 40 of the initial 200 passed this second test.

(Given how closely related rats and mice are, this drop suggests both that some of the initial positive results were probably accidents of the experimental procedure and that regulatory RNAs evolve new functions rather quickly. This later point would be in keeping with the findings on human evolution we mentioned just above.)

Next, the authors inserted some of the most effective RNAs into cardiac muscle cells obtained from mature animals, after cell division has stopped entirely. Again, they worked. After a short delay, the cells started dividing again, slowly creating a larger population of cells. Accompanying this, the authors saw some indication that the cells had decreased their specialization and changed the expression of genes that are normally associated with mature cardiac muscle. This shouldn't be enough to cause defects in cardiac function, though, given that they still looked more like specialized cardiac muscle than the cells of a newborn heart, which clearly need to be functional.

Since everything worked well in culture, the authors tested some of the most effective RNAs in the hearts of mature rodents. Again, it seemed to work; cells started showing signs of dividing. More significantly, it worked well on a damaged heart. After subjecting mice to a procedure that mimics a cardiac infarction, the authors induced the remaining cardiac cells to express the RNA. By nearly every measure, the hearts treated with RNAs maintained more of their normal function than controls did and an examination of the hearts revealed many more cardiac muscle cells and far less scar tissue.

The researchers also looked into the changes in gene expression that accompanied this return to proliferation. As expected, they were numerous: over 1,500 genes had altered levels of expression for each of the two RNAs tested. And to a large extent, they didn't overlap, suggesting that the two regulatory RNAs exert their effects by tweaking cells in very different ways. Targeting some of these 1,500 genes individually could boost cell proliferation, but the effect wasn't as strong as when the micro-RNAs were inserted into the cells.

So, clearly the networks downstream of these RNAs are pretty complicated, and it will take some significant effort to sort out. But in the mean time, the RNAs suggest that it might be possible to develop therapies without needing to know how, precisely, they work. The relative rarity of shared function between the mouse and rat suggests that very few (if any) of the RNAs identified in this screen would work in humans. But, with the logic of the screen clearly established, then it should be possible to reproduce it in human cells (presumably those derived from stem cells).

The big hurdle then would probably be safety. It's probably impossible to target these micro-RNAs specifically to heart cells. Inducing cell division in off-target cells is never a good idea, and it's possible that in different tissue these micro-RNAs could cause completely unexpected behavior. It's also clear that the cardiac cells that do pick them up will have somewhat altered function—not necessarily a good thing during the recovery from heart problems. Given those issues, waiting for a better understanding of how these RNAs work might not be a bad thing.

There are some gene therapy vectors that have been shown, at least preclinically, to target cardiomyocytes extremely efficiency and with a fairly high degree of selectivity. One of these is adeno-associated virus (vector) serotype 9 - check out a Pubmed search of "heart" and "aav9" (http://www.ncbi.nlm.nih.gov/pubmed?term=aav9%20heart). The nice thing about AAV vectors, in this instance, is that they don't integrate into the genome, so that subsequent cell divisions would dilute/silence the AAV vectors so the effect might "wear off" after a while.

I get the sense that this is very black box at the moment...they've empirically determined something that seems to work in restarting cell division, but do not have the theoretical framework for why it happens.

The research that goes into finding out the "why" should be what becomes the focus of future funding.

In practice, in the near term, this statement is likely true and the big weakness with the approach. But, its surely not true in theory. Nor is it likely to be true in practice when biological engineering techniques mature. The clock for that maturation is likely to be measured in decades. In the meantime most of the talk about the whole range of techniques is likely to turn out to be mostly hype. But, it is only a matter of time before people figure out how to engineer biological agents that are able to target specific cell types with a variety of therapies that control the operation of existing genes or introduce new ones.

How true that you are! If anybody has lost a loved one you can't replace what has been broken, btw, very good article on the possibility of mending someone's heart, I'm that when this tech comes true, no thanks in the world could even come close for that person who mends them...

Considering evolution is one of the lies from the pit of hell, I'm forced to hope this doesn't ever go before Congress or need federal funds to progress.

Just explain to them that it'll help them after they have heart attacks. Nothing puts the fear of death into old white guys like the fear of a heart attack.

It seems to me like kicking off cell division would also increase the risk of cancer as well, would it not? I guess if you're already had a heart attack though it may be a minor risk compared to getting your heart working properly again.

There are some gene therapy vectors that have been shown, at least preclinically, to target cardiomyocytes extremely efficiency and with a fairly high degree of selectivity.

Very true, and that's highly relevant to this work. But I thought AAV9 also had selectivity for musculoskeletal tissue. I suspect any therapy (which would only be commenced 3-6 months after the heart attack when stability has been regained) would consist of a selective vector combined with intra-coronary delivery. If they could tag on some sort of metabolic instability to reduce its plasma half-life that would be a bonus.

While the scientist in me finds this fascinating stuff, though, I'm all-too-aware that if this ever saw the light of day as a treatment it would be at a cost that'd make Rheumatoid Biologicals look like plastic toys from a discount store.

There are some gene therapy vectors that have been shown, at least preclinically, to target cardiomyocytes extremely efficiency and with a fairly high degree of selectivity.

Very true, and that's highly relevant to this work. But I thought AAV9 also had selectivity for musculoskeletal tissue. I suspect any therapy (which would only be commenced 3-6 months after the heart attack when stability has been regained) would consist of a selective vector combined with intra-coronary delivery. If they could tag on some sort of metabolic instability to reduce its plasma half-life that would be a bonus.

While the scientist in me finds this fascinating stuff, though, I'm all-too-aware that if this ever saw the light of day as a treatment it would be at a cost that'd make Rheumatoid Biologicals look like plastic toys from a discount store.

I'm not convinced that a high proportion of the vector particles meet their cognate receptors on first pass of the circulation so I'm a bit skeptical about the value of a coronary delivery. Perhaps a simple intravenous injection combined with something like you suggest (i.e. a tag for rapid plasma degradation) might be a more elegant solution, albeit one which I don't think has been shown yet.

Considering evolution is one of the lies from the pit of hell, I'm forced to hope this doesn't ever go before Congress or need federal funds to progress.

Obvious troll is obvious.

I get the sense that the key here is to develop ways to test gene therapies without using people as test subjects. We know that some of these micro-RNAs work, but figuring them out is practically improbable without a good way to actually test them on heart cells. If scientists can develop general ways to test new therapies, then this could open up a lot of possible cures, not just regrowing heart cells. I still think that stem cells are the best path right now, but imagine being able to inject some micro-RNA into a person's spinal cord and having it repair itself. Please bring us more stories like this, Ars!

I'll bet that candidates for heart transplants with little hope of getting one will volunteer for testing the micro-RNA therapy. Assuming that they can identify the micro-RNA groups that could possibly work, the problem would probably be too many volunteers as opposed to not enough.

While this may help patients in the short term, stem cells may be more viable. Unless I have this wrong, and I certainly may, forcing an old heart cell to divide will heal damage, but you are healing it with tissue that remains old and essentially worn out.

My understanding, from grad school, was that, surprisingly, mice and rats are not actually that similar genetically and that mice are much closer to other species.This surprised me because they look so similar.

So, the comment that these miRNAs may not work in humans may not be true.Of course, I wouldn't be surprised if they didn't. It's just something to think about.

Considering evolution is one of the lies from the pit of hell, I'm forced to hope this doesn't ever go before Congress or need federal funds to progress.

Obvious troll is obvious.

I get the sense that the key here is to develop ways to test gene therapies without using people as test subjects. We know that some of these micro-RNAs work, but figuring them out is practically improbable without a good way to actually test them on heart cells. If scientists can develop general ways to test new therapies, then this could open up a lot of possible cures, not just regrowing heart cells. I still think that stem cells are the best path right now, but imagine being able to inject some micro-RNA into a person's spinal cord and having it repair itself. Please bring us more stories like this, Ars!

I don't think he was trolling but rather just having a go at the US government in relation to the way they handle science.

What disappoints me about this discovery is that there is still so much more work to do to get it to the human testing stage. But it is still very interesting nonetheless.

Yay! Glad some of the scientific research made in Trieste (smallish town in the north-eastern part of Italy) made Arstechnica's front page!Trieste has been at the forefront in Italy in the treatment of cardiac arrest for some time.

Nobel prize worthy stuff. This may turn out to enable us all to live longer, healthier lives.

That's not saying much since they gave one to Gore and Obama. But yeah further on down the road it will allow many heart-attack survivors to have their hearts restored to full strength. I'm hoping they will be able to do this for those who have suffered spinal cord damage.

I get the sense that this is very black box at the moment...they've empirically determined something that seems to work in restarting cell division, but do not have the theoretical framework for why it happens.

The research that goes into finding out the "why" should be what becomes the focus of future funding.

Not disputing your point here, but basic vs applied research funding is a fascinating trade off. Of course, basic research is always easy to dismiss as impractical, having low prospects of short-term payoffs, etc. and therefore deserves support.

However, it's also important to keep in mind that living biological systems are the most complex things we are aware of. Really complex problems seem to have the property of resisting progress in understanding by throwing more resources at the problem, progress seems to come as much from gifted insight and serendipity as by careful, meticulous work.

It's worthwhile to remember that nearly all progress in medical treatment to date has come by allowing that our fundamental understanding of how all the pieces go together isn't available yet, and by just seeing what happens when we press the buttons we have access to.

I find work like this and related work on how the human body repairs, ages and deteriorates on a molecular/genetic level to be absolutely fascinating. I feel like it won't be too long into the future when we will have gained the understanding to drastically slow, halt, or even reverse the aging process for many of the body's major systems. I just hope it's fairly soon so I can get stuck at a fairly young biological age.